Enhanced Delivery of Rituximab In Combination with Methotrexate-Based Blood-Brain Barrier Disruption for Patients with Newly Diagnosed Primary CNS Lymphoma.

Primary CNS lymphoma (PCNSL) is a rare, aggressive, primarily large B-cell lymphoma confined to the CNS and/or eyes at presentation. High-dose (HD) methotrexate (MTX) - based chemotherapy is standard of care in PCNSL and when combined with enhanced delivery results in extended survival without cognitive loss. The addition of rituximab to HD MTX regimens for B-cell PCNSL is widely used primarily by analogy to the positive results attained in systemic B-cell lymphomas. However, recent pre-clinical and clinical use of single agent rituximab provides stronger rationale. Efficacy has been shown using single agent rituximab in nude rats with intracerebrally implanted MC116 human B-cell lymphoma cells, and in patients with recurrent PCNSL by using ¹¹¹In-ibritumomab to assess delivery and ⁹⁰Y-ibritumomab to assess efficacy. Next, safety and efficacy of enhanced delivery of rituximab with MTX-based blood-brain barrier disruption (BBBD) was shown in patients with recurrent PCNSL. Based on these results, we treated patients with newly diagnosed PCNSL with rituximab in combination with MTX-based BBBD.

IRB permission was obtained to retrospectively evaluate patients with newly diagnosed B-cell PCNSL, treated with rituximab in combination with MTX-based (intra-arterial [i.a.]) BBBD chemotherapy as first-line treatment. Treatment consisted of MTX (2500mg/day, i.a.) and carboplatin (200mg/m²/day, i.a.) with BBBD, for 2 consecutive days every 4 weeks for up to one year. Rituximab (375mg/m², i.v.) was given every 4 weeks, 12 hours prior to the MTX with BBBD treatment. Objective response rate, progression free survival (PFS), overall survival (OS), and toxicities were evaluated.

Twelve patients (7 female, 5 male) were treated between April 2003 and October 2008. The median age was 65 years (min 49, max 75); 10 patients were older than 60 years. The median Karnofsky Performance Score (KPS) prior to treatment was 55 (min 20, max 80). All patients had brain parenchyma involvement at presentation. Additionally, CSF cytology was positive in 2 patients and one patient had ocular involvement. One patient with pre-existing cardiac disease died 2 weeks after initiation of MTX without BBBD due to myocardial infarction and was not evaluable for response. The overall response rate was 83% (7 CR, 1 CRU, 2 PR, 1 SD). The median PFS was 3.47 years (95% CI: 0.42, not yet attained) and the 2-year PFS in this cohort is 73%. The median OS was 4.42 years (95% CI: 0.28, not yet attained). Eight patients who attained CR or CRU were alive at data-cut-off; 6 of the 8 patients remain in CR 2 years or more after diagnosis. The most frequent toxicities were hematologic. Eight (67%) patients developed grade 3 or 4 hematologic toxicity and 7 (58%) developed grade 3 infection.

We previously reported a 2-year PFS of 50% with 25% survival at 8.5 years in 149 newly diagnosed PCNSL patients treated with MTX-based BBBD without rituximab. The addition of rituximab shows manageable toxicity and provides sustained duration of CR in newly diagnosed PCNSL, with 10 of 12 patients over 60 years old and a median KPS of 55. These pilot data suggest the 2-year PFS may be increased to 70% or more with the addition of rituximab to MTX-based BBBD chemotherapy. A multi-center phase II prospective study is underway.

No relevant conflicts of interest to declare.